On My Youngest Daughter Ai Hsing (Front) Graduation Day

On My Youngest Daughter Ai Hsing (Front) Graduation Day

Saturday, October 15, 2016

Magnetic Nano Particles to Open Gates to Brain-Blood Barrier

Dear Professor Dr.  Andrew Charles Gomes

Thank you for your question soliciting my coments on this website:

I am not an expert in this area of medicine – nano-medicine, or in nano-pharmacodynamics or its kinetics.  

But still,  I shall attempt in a simple, non-technical way to answer your question by  explaining  its mechanisms as a potential drug-delivery system especially in hard-to-access target areas such as the brain where concentrated drug dosage need to be delivered without compromising toxicity exceeding therapeutic index / therapeutic  windows to the rest of the body especially for cytotoxic agents in cancer treatment.

Brief Introduction:

The application of nanotechnology as a drug delivery system especially in cancer research and in other therapeutics is considered as nanomedicine. This  discipline is one of the most active and exciting areas of medicine scientists are actively working on today.

It applies nanotechnology to highly specific medical  and pharmacological interventions for the prevention, diagnosis and treatment of diseases. The haste in nanomedicine research over  the past few decades is now  recognized  as part of translational medicine  that may result in  considerable marketing efforts  by  bio-pharmaceutical companies throughout the world.

There are at present a significant number of products using nanotechnology  such as cosmetics on the market and an increasing numbers are  in the pipeline. Presently, nanomedicine is restrained to drug delivery systems, and the results of R & D in this areas has exceeded  75% of total nanotechnology sales.

However, the application of nanotechnology as an emerging drug delivery systems would depend on their safety and efficacy data, but I believe would fail to reach clinical development for other therapeutic regimens because of their poor biopharmacological properties, such as modest solubility or poor permeability across the brain-blood barrier or even through the intestinal epithelium, circumstances that translates into poor bioavailability and undesirable pharmacokinetic  end-points.   

Currently there exist various nanoforms that have been attempted as drug delivery systems. They vary from metallic-organic conjugates,  biological compounds, such as albumin, gelatin and phospholipids in liposomes complexes, to chemical compounds  such as various polymers and solid metal-congugated complexes.

Polymer–drug conjugates, which have high-small size spectrum are normally not considered as nanoparticles(NPs).  But since their size can still be structured within 100 nm, they have been  integrated into these nanodelivery systems. 

These nanodelivery systems can be designed to have drugs absorbed or conjugated onto the particle surface, encapsulated inside the polymer/lipid bonds or dissolved within the particle matrix including perhaps magnetic –sensitive NPs which is the question Professor Dr.  Andrew Charles Gomes, a Senior Consultant ENT Surgeon associated with Johns Hopkins Hospital was asking me to comment

Brain-Blood Barrier:

First, we must consider the existence of  blood–brain barrier (BBB) which is a highly selective permeability barrier that disconnects the circulating blood from the brain extracellular fluid in the central nervous system (CNS).

This blood–brain barrier is shaped out by the brain endothelial cells, which are then linked by tight junctions with an extremely high electrical resistivity.

Neurophysiologists know that the blood–brain barrier allows only the passage of water, some gases like oxygen and carbon dioxide,   and lipid-soluble molecules into the brain.  These molecules are transported by passive diffusion, as well as the selective transport of compounds such as glucose and amino acids that are critical for neurological function.

On the other end of the blood–brain barrier it may prevent the entry of lipophilic, potential neurotoxins by way of an active transport mechanism mediated by P-glycoprotein.

Astrocytes are essential in this barrier mechanism to create the blood–brain barricade. A small number of regions in the brain, including the circumventricular organs (CVOs), do not have a blood–brain barrier such as what Prof Dr. Andrew Gomes emailed me on the above website.

However, there  are  regions in the brain where there is an open gate, and where  certain “thermo-gates” are temporary opened  at certain temperatures.  It is here scientists take an advantage when the gates are opened and / or subjected to a magnetic field for drug-laced nanoparticles to gain entry.

Normally, the blood–brain barrier exists along all capillaries and consists of tight junctions around the capillaries, but do not exist in normal circulation. Endothelial cells restrict the diffusion of microscopic objects such as bacteria and pathogens, and large or hydrophilic molecules into the cerebrospinal fluid (CSF), but  allowing the diffusion of small or hydrophobic molecules  such as oxygen,  carbon dioxide and hormones.

It is in these regions of the brain t that actively transports nutrients such as glucose and specific range of proteins across the barricade which encompasses a thick basement membrane and astrocytic sheet.

This "bio-barricade” results from the selectivity of the tight junctions between endothelial cells in CNS vessels restricts the passage of even solutes which generally are not magnetic-sensitive

At the interface between blood and the brain, endothelial cells are sewed together by these tight junctions. These junctions are composed of smaller subunits, frequently biochemical dimers, that are trans-membrane proteins such as occludin, claudins, junctional adhesion molecules.

The units of these trans-membrane proteins are fastened into the endothelial cells by another protein complex that includes other associated proteins. None of these molecules to the best of my understanding can be subjected to magnetic induction.

As I have already explained, the blood-brain barrier is a highly selective semipermeable barrier running inside the majority of all the vessels in the brain, and they only that lets through water, some gases and a few other select molecules, while inhibiting potentially toxic elements in the blood from entering the brain.  

It is almost improbable for most drugs to get through excepts perhaps Levodopa, the drug  used in the management of Parkinson’s  disease.  Levodopa is probably  the best drug that mimic dopamine,  the natural neurochemical in the brain

No Entry:

Scientists currently tell us 98 percent of therapeutic molecules are also blocked by the brain-blood barrier.

However medical researchers have developed a technique using magnetic nanoparticles to open  the door for such molecules, and in so doing opening the gates  to new therapeutics  regimen for brain diseases.

"At the present time, surgery is the only way to treat patients with brain disorders," says Anne-Sophie Carret, a study senior author in this area of magnetic nano-therapeutics  

Currently surgery is the only option to remove certain kinds of tumors.  But some disorders are located in the brain stem, amongst nerves;  making surgery impossible says Anne-Sophie Carret.

By opening the blood-brain barrier to these therapeutic molecules, the researchers feel that  would provide an alternative to surgery for treating various brain diseases.

According to researchers the technique involves sending magnetic nanoparticles to the surface of the blood-brain barrier at the desired location in the brain. The researchers say this could be achieved using magnetic resonance imaging (MRI) technology, albeit a different method was used for their study.

Scientists in the study say that the drug-laced nanoparticles are directed to the desired location, the nanoparticles are then exposed to a radio-frequency field that caused them to dissipate heat.

This causes a small rise in temperature which in turn places mechanical stress on the barrier, thus opening  a localized gate  which allows therapeutic molecules to pass through. The opening is only temporary, remaining open for around two hours the researchers claimed.

"While other techniques have been developed for delivering drugs to the blood-brain barrier, they either open it too wide, exposing the brain to great risks, or they are not precise enough, leading to scattering of the drugs and possible unwanted side effect," says principal investigator Sylvain Martel.

Currently technique is experimental, and was developed using murine (rats and mice) models. It is yet to be tested on humans, but the researchers are optimistic that  one day it can be used  on humans.

"Although our current results are only proof of concept, we are on the way to achieving our goal of developing a local drug delivery mechanism that will be able to treat oncologic, psychiatric, neurological and neurodegenerative disorders, amongst others," says Carret.

To the best of my understanding at the time of writing this comment, this is a novel approach in breaking into the brain-blood barrier using magnetically-induced nano therapeutic molecules, but the question I  would like to  ask the researchers is, how then would these drug-tagged nanoparticles get out from the brain parenchyma once it has delivered its therapeutic molecules to the target region. Surely, the brain-blood barrier is only a one-way street.

One-Way Entry:

Drugs, especially metallic complexes and large molecules with high molecular weights cannot find their way into the general blood  circulation or cerebrospinal fluid (CSF) flow  even via active transport mechanisms,  let alone by diffusion especially if a one-way gate is closed once the nanoparticles get lodged inside the brain  This is the dilemma I need to ask my scientific-medical counterparts . I wonder what their answers would be as much as I like to direct this same question to  Professor Andrew Charles Gomez.

A Neuro-Scientist Opnion:

I had a discussion with Professor Dr. Ong Wei Yi, who is my nephew and a neuroscientist at Yong Loo Lin School of Medicine, National University of Singapore (NUS) at a family dinner on September 3, 2016.

I was talking about the use of nano-delivery cream in cosmetic application such as in sun screens,  and my nephew  cautioned me about the use of nanoparticles, depending on their size as they can lodge in the brain even by inhalation, but not by injection, probably because  of this brain-blood-barrier mechanisms,   and they can cause extensive neurodegeneration and wide spread tissue and organ damage according to Professor Ong Wei Yi.

This is my nephew’s professional opinion as a neuroscience expert at NUS.

Many Questions:

I too have many questions to ask on their biosafety that requires extensive and long-term toxicological evaluation and long-term clinical trials with safety and dose data clearly demonstrated -  right to the end of Phase Four of drug trials before magnetic  nano therapeutic molecules can find their way into clinical applications

Comments by ju boo lim (lim ju boo) 

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